Worldwide, colorectal cancer is the third most common cause of death in cancer and approximately one million individuals are diagnosed each year. Despite optimal surgical treatment and modern adjuvant chemotherapy, half of patients have recurrences and ultimately die within 5 years from diagnosis. The most important prognostic factors are presence of lymph node or distant metastases, being found in about 50% of all cases. Patients with locoregional lymph node metastases, Duke's C/stage III, have about 60% 5-year survival after surgery, and when distant metastases are present, the 5-year survival rate is less than 10%. The established, adjuvant treatment in stage III patients is 5-Fluorouracil (5-FU)-based chemotherapy, improving absolute 5-year survival by approximately 10%. There is no evidence for a statistically significant survival benefit for chemotherapy in Duke's B/Stage II patients. However, 20% of patients being classified as lymph node-negative will suffer from recurrent disease. Some of these patients are likely to be understaged, since it is widely accepted that accurate staging of colon cancer is difficult and heavily dependent on the number of lymph nodes analyzed by the pathologist. The sentinel node, originally defined in penile carcinoma, is the first lymph node to receive lymphatic drainage from a tumor. Sentinel node detection and analysis has recently been applied in colon cancer, improving staging considerably.
The immune system often appears informed about tumors, as shown by an accumulation of immune cells at tumor sites, which correlates with improved prognosis. Two different models for the immune response to tumors have been proposed: the concept of immunosurveillance and the danger model. According to the immunosurveillance hypothesis, tumors expressing antigens are regarded as “non-self” by the immune system, and a major function of the immune system is to survey the body for the development of malignancy and to eliminate tumor cells as they arise (Burnet (1970) Prog. Exp. Tumor Res. 13:1-27). To detect “danger,” the immune system uses professional antigen-presenting cells (APC) as sentinels of tissue damage. In the presence of danger signals, APC (e.g., dendritic cells, activated macrophages, and B cells) stimulate the T cell response. The danger model proposes that cancer cells do not appear dangerous to the immune system, so that the response of T cells to tumors is not initiated (Fuchs & Matzinger (1996) Semin. Immunol. 8:271-280).
Natural killer (NK) cells of the innate immune system also play an important role in immune surveillance of tumors (Smyth, et al. (2001) Nat. Immunol. 2:293-99). NK cells kill MHC class I-deficient cells, a phenomenon that is part of the “missing self” hypothesis (Watzl & Long (2000) Nat. Med. 6:867-8; Pardoll (2001) Science 294:534-6). The activity of NK cells is controlled by a balance of positive and negative signals. Engagement of inhibitory receptors by MHC class I molecules blocks activation signals. Two families of inhibitory receptors have been identified in humans: the immunoglobulin-like killer cell inhibitory receptors and the lectin-like CD94-NKG2 receptors. Stimulatory receptors include receptors (e.g., CD16, CD94-NKG2C, natural cytotoxicity receptors) that are supposed to bind to constitutively expressed ligands (Moretta, et al. (2000) Immunol. Today 21:228-34) and NKG2d receptors, which bind to molecules that are induced by cellular stress (Cerwenka, et al. (2000) Immunity 12:721-7; Bauer, et al. (1999) Science 285:727-9; Wu, et al. (1999) Science 285:730-2). Ligands for NKG2d receptors are the MHC class I chain-related (MIC) glycoproteins MICA and MICB in humans and the minor histocompatibility antigen H60 and the retinoic acid early inducible (Rae-1) family in mice.
Additional cells of the innate immune system involved in immunity against tumors are macrophages and neutrophils (Lollini & Formi (1999) Immunol. Today 20:347-350; Di Carlo, et al. (2001) Blood 97:339-45; Elgert, et al. (1998) J. Leukoc. Biol. 65:275-90; Bonnotte, et al. (2001) J. Immunol. 167:5077-83). These cells can reject tumors by direct killing of the tumor cells, by destruction of tumor vessels and matrix, and by inhibition of angiogenesis. Moreover, they display tumor antigens and can stimulate other immune cells such as CTL, NK cells, or APC. In contrast, inflammatory cells may also contribute to tumor progression by production of tumor growth factors and stimulation of angiogenesis (Lin, eta l. (2001) J. Exp. Med. 193:727-40). Macrophages and neutrophils are recruited to the tumor site by expression of adhesion molecules on endothelial cells and by chemotactic proteins.
In the adjuvant setting, tumor immunotherapy offers an appealing alternative to traditional cytostatics. One strategy has been to expand and activate NK cells in vitro without specific antigen by culturing with IL-2 followed by infusion of large numbers of these NK cells back into patients alone or with high doses of IL-2. This approach, or administration of high doses of IL-2 to expand and activate NK cells entirely in vivo, has yielded antitumor activity and remission in a subset of patients (Rosenberg, et al. (1993) J. Natl. Cancer Inst. 85:622). However, life-threatening toxicity often develops, largely due to the release of tumor necrosis factor (TNF) from activated NK cells. Other attempts to stimulate the innate specific T cell immunity have been done by different types of vaccines. Promising results from animal studies entailed a study in which autologous tumor cells and an adjuvant immunomodulating agent, Bacillus Calmette-Guerin (BCG) was given in combination several times to 98 patients with colorectal cancer in a prospectively randomized study (Hoover, et al. (1993) J. Clin. Oncol. 11:390-9). No statistically significant differences were detected in survival; however, a small decrease in recurrence rate in stage II colon cancer patients was observed. Further studies were done but no statistical clinical benefit in disease-free interval or survival could be seen, not even when combined with 5-FU and Leucovorin.
A synbiotic containing Lactobacillus rhamnoses GG and Bifidobacterium lactis Bb12 and oligofructose-enriched inulin has been suggested to alter certain colorectal cancer intermediate biomarkers, and reduce colorectal proliferation (Liong ((2008) Int. J. Mol. Sci. 9:854-863). Further, heat killed cells of L. plantarum, L. delbrueckii ssp. bulgaricus, L. salivarius ssp. salivarius, B. longum and L. plantarum have been shown to reduce the viability of HT-29 colon cancer cells, whereas L. plantarum, L. acidophilus, L. salivarius ssp. salivarius, B. longum and B. infantis have been shown to reduce the viability of Caco-2 colon cancer cells (Liu & Pan ((2010) J. Food Drug Analysis. 18:77-86).
US 2011/0206721 teaches a dietary supplement provided in powder form, which includes a mixture of mushrooms grown in fermented soy and curcumin, for use as a chemopreventive in colon cancer. The inclusion of an edible mushroom such as Lentinus edodes or mushroom ingredient thereof, or lychee powder is also suggested.